2014 Pathway Initiator Awardee Michael D. Dennis, PhD

Determining how high blood glucose leads to blindness

Project title: Hyperglycemia-Induced Translational Control of Gene Expression in the Retina
Institution: The Pennsylvania State University College of Medicine
Pathway project publications: 9
Promoted to first independent faculty position as assistant professor in 2015

Major accomplishments:

To date this project has supported nine published manuscripts. Three of these were the first from my independent laboratory. Early in my postdoctoral training, I discovered that high blood glucose levels activate a molecular switch that changes which genes are translated into proteins.  Vascular endothelial growth factor (VEGF) is one of the proteins that is increased in the presence of high blood glucose levels. VEGF causes blood vessels in the eye to multiply abnormally, and these dysfunctional blood vessels contribute to the development of retinopathy.  My Pathway studies demonstrate that one of the key factors involved in activating the switch is a protein called 4E-BP1. Compared to regular laboratory mice, mice that do not have the 4E-BP1 protein are protected from early development of diabetes-induced vision loss, which instead presents much later in diabetes disease progression in these mice. Thus, by therapeutically targeting 4E-BP1, we hope to address diabetes-induced changes in hundreds of growth factors and cytokines, thereby moving beyond the current therapeutics that have proven largely insufficient in addressing the neurovascular complications that result from diabetes.

Impact statement:

I am committed to this project because the scope of the problem it aims to address is vast and devastating. Most people with diabetes will develop some form of retinopathy within two decades of diagnosis.  Current clinical interventions largely address symptoms, rather than the underlying causes of diabetes-induced vision loss.  This project is an attempt to move beyond the current single cytokine targeted approaches by identifying the molecular cause of changes in gene expression profiles in the retina.  As a result of receiving the Pathway award, I was able to explore this exciting research direction with the appropriate scientific mentoring, career development activities, and professional interactions necessary to complete my postdoctoral training.

Through this award, I was able to obtain an independent investigator position at Pennsylvania State University College of Medicine, where my laboratory specifically focuses on understanding how diabetes causes vision loss.  During the transition process, I received competitive offers for tenure-track Assistant Professor positions at multiple academic institutions that included newly renovated independent laboratory and office space, generous start-up funds, and ample protected research time.  In addition to supporting my position, funds from the Pathway award also help to support a research assistant and graduate student that work in my laboratory. 

Overall the Pathway award has been critical in pursuing my long-term goal of identifying new interventions that address the molecular basis of diabetic retinopathy and ultimately improving the lives of people affected by diabetes.